Catheter Balloon Drug Adherence Techniques and Methods

ABSTRACT

Various methods for optimizing coating of medical devices, such as balloon catheters are disclosed. One method configures catheter balloon folds based on balloon diameter and volume. Other methods include using a specifically-sized protective sheath, using a vacuum, using pressure, pulling the balloon through a coating solution, using at least one spacer or a wick between at least one fold for metering a therapeutic coating into the folds of the balloon, placing an intermediate layer between the balloon and the therapeutic coating, placing a soluble film having a therapeutic agent around the catheter balloon or inside the folds, and any combination thereof. Balloon catheters and catheter balloons having a specific folding configuration, a specifically-sized protective sheath, an intermediate layer, or a soluble film are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims priority to U.S. Provisional PatentApplication No. 61/049,448 filed on May 1, 2008.

FIELD OF THE DISCLOSURE

Embodiments of the present disclosure generally relate to coated medicaldevices and methods for coating medical devices. More particularly,embodiments of the present disclosure relate to percutaneoustransluminal angioplasty balloon catheters coated with a therapeuticagent and methods for coating percutaneous transluminal angioplastycatheter balloons.

BACKGROUND

The following background information is provided to assist the reader tounderstand embodiments disclosed below and the environment in which theymay be used. The terms used herein are not intended to be limited to anyparticular narrow interpretation unless clearly stated otherwise, eitherexpressly or impliedly, in this document.

Medical devices, such as percutaneous transluminal angioplasty (PTA)balloon catheters, are often coated with various agents, including forexample therapeutic agents, radiopaque materials, lubricious materials,hydrophilic materials, and biocompatible materials. PTA is a medicalprocedure that is used to reduce or eliminate blockages within thevascular system in order to relieve clinical symptoms associated withreduced blood flow to an organ or region of the body. PTA works byplacing a non-elastomeric balloon within a blockage or narrowing andinflating it with sufficient force to restore blood flow to the distalanatomy. The balloon both compresses and expands the atheroscleroticplaque to effectively enlarge a previously constricted lumen. Thisprocedure has become a primary therapy for treatment of occlusivevascular disease.

Unfortunately, PTA has a very high incidence of restenosis, sometimesexceeding 50%. In some circumstnaces, a bare metal stent (BMS) or a drugeluting stent (DES) is placed at the site of the plaque after PTA toprevent restenosis. A BMS reduces the incidence of restenosis toapproximately 20% and although DES's are not currently approved for theperipheral arteries, a DES can reduce restenosis to less than 5% in thecoronary arteries. While a DES is the preferred method of treatment ofocclusive vascular disease (OVD) in the coronary arteries currently,problems related to late restenosis and late in-stent thrombosis havebeen noted with DES. In addition, the patient must remain onantiplatelet and anticoagulant therapy for an extended period of timeafter the procedure. Therefore, there is a need for alternate orimproved therapies for the treatment of OVD. Recent therapies involvethe use of drug coated PTA catheter balloons, with or without a baremetal stent, for the delivery of the drug at the lesion site to preventrestenosis.

Standard methods for coating PTA catheter balloons, such as dip coating,have several drawbacks. For example, the coating is inconsistent,non-uniform, and shreds away during handling. In addition, the processis very labor intensive, lengthy, and environmentally unfriendly. Thus,there is a continued need for improved PTA catheter balloons and methodsof coating catheter balloons providing uniform and consistent deliveryof effective dosages of therapeutic agents to target locations withreduced systemic dosages as well as reduced manufacturing costs.

SUMMARY

In general, various embodiments of the present disclosure are directedto methods for optimizing coating of medical devices, such as ballooncatheters, including metered and consistent concentrations oftherapeutic agents. Various embodiments of the present disclosure arealso directed to catheter balloons and PTA catheters with optimizedcoating features.

In one embodiment, a method of folding a catheter balloon for optimizingcoating of the balloon is disclosed. The number of folds is configuredfor a specific balloon diameter and a volume of coating compositionnecessary to achieve a target concentration, such as a therapeutic agenttarget concentration. A balloon catheter and a folded catheter balloonwith a specific number of folds based on the balloon diameter and volumeare also disclosed.

In another embodiment, a substantially specifically-sized protectivesheath for a given balloon diameter with optional spiral slits isdisclosed. The specifically-sized protective sheath may be placed overthe balloon before or after coating of the balloon. Thespecifically-sized protective sheath aids in metered methods of coatingcatheter balloons as well as coating distribution and protection.

Various embodiments related to optimizing coating of catheter balloonsinclude using a vacuum, pressure, pulling the balloon through a coatingsolution, optimization of the concentration of a therapeutic coatingsolution, using at least one spacer or a wick within at least one foldfor metering the coating solution into the folds of the balloon, placingan intermediate layer between the balloon and the coating, placing asoluble film comprising a therapeutic agent around the catheter balloonor inside the folds, and any combination thereof. In additionalembodiments, balloon catheters and catheter balloons having anintermediate layer or a soluble film are disclosed.

Those and other details, objects, and advantages of the presentdisclosure will become better understood or apparent from the followingdescription and drawings showing embodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate examples of embodiments of thedisclosure. In such drawings:

FIG. 1 is a general schematic diagram of a PTA balloon catheter;

FIG. 2 depicts an injection method for coating the outside surface of acatheter balloon;

FIG. 3 depicts an injection method for coating inside a catheter balloonfold;

FIG. 4 is a cross-sectional view of a folded balloon;

FIG. 5 is a cross-sectional view of a folded catheter balloon enclosedby a specifically-sized protective sheath;

FIG. 6A and FIG. 6B depict a slotted protective sheath (FIG. 6A) and anon-slotted protective sheath (FIG. 6B) enclosing a catheter balloonusing a ratcheting mechanism and securing with closing bands;

FIG. 7A and FIG. 7B depict a balloon catheter in a pressurized chamberfor pressurized dip coating (FIG. 7A) and a cross-sectional view of thefolded balloon in the pressurized chamber at position 7A-7A (FIG. 7B);

FIG. 8 is a cross-sectional view of a catheter balloon being coated byrotation in a coating solution in a direction that slightly opens theballoon folds while substantially simultaneously being pulledlength-wise;

FIG. 9 is a schematic diagram of aluminum rod spacers used to hold thefolds of a catheter balloon open during coating;

FIG. 10 is a cross-sectional view of a catheter balloon with a wickinserted into the folds of the balloon for drawing a coating solutioninto the folds;

FIG. 11 is a schematic diagram of a catheter balloon with anintermediate layer between the balloon and a coating;

FIG. 12A-FIG. 12I are schematic diagrams of a catheter balloon coatedwith a soluble film with FIG. 12A and FIG. 12B depicting soluble filmapplied post pleating prior to folding of the balloon, FIG. 12Cdepicting soluble film applied post folding of the balloon in the folds,FIG. 12D depicting soluble film applied around the outside, FIG. 12Edepicting a combination, and FIG. 12F through FIG. 12I depicting solublefilm applied in various configurations prior to pleating and folding theballoon; and

FIG. 13 is a graph depicting efficacy results from a coatingspecification study.

DESCRIPTION

In all of its embodiments and related aspects, the present disclosuremay be used with medical devices, including, for example, PTA ballooncatheters. Other examples of medical devices include, withoutlimitation, drainage catheters, replacement or artificial venous values,aortic valves, replacement valves, ventricular catheters,ventriculostomy balloons, balloon expandable stents, and coronaryballoons.

Medical devices are routinely coated with compositions including, forexample and without limitation, therapeutic agents, radiopaquematerials, radioactive materials, polymeric materials, sugars, waxes,fats, and lubricious materials. As used herein, “therapeutic agent”includes, but is not limited to, any therapeutic, for example drugs,genetic material, and biological material. Genetic material includes forexample, without limitation, DNA or RNA, viral vectors and non-viralvectors. Biological material includes for example, without limitation,cells, bacteria, proteins such as growth factors, peptides, lipids, andhormones. Drugs include, without limitation, anti-thrombogenic agents,anti-proliferative agents, anti-inflammatory agents, without limitation,anti-thrombogenic agents, anti-proliferative agents, anti-inflammatoryagents, anti-neoplastic agents such as epotilone and its derivatives,antimiotic agents, antioxidants, anti-coagulants, immunosuppressantssuch as sirolimus and its derivatives, vascular cell growth promoters,vascular cell growth inhibitors, antibiotic agents, angiogenicsubstances, restenosis-inhibiting agents, and drugs for heart failure.The “therapeutic agent” may include a combination of one or moretherapeutics. Particular embodiments include restenosis-inhibitingagents such as Taxol, paclitaxel, paclitaxel analogues, derivatives, andmixtures thereof. The coatings can be in solid, liquid, or gas formsdepending on the method used to coat the device. In an example, carriersmay be used with the therapeutic, such as, for example and withoutlimitation, bioabsorbable agents, microspheres, microtubes, andphysiologically compatible non-reactive drug transfer or radio opaqueagents, such as urea, iopromide, cremophore EL, vitamin E, TocopherylPolyethylene Glycol Succinate (TPGS), etc.

Various embodiments described herein pertain to a PTA catheter balloonthat has a specialized coating containing a therapeutic agent. The PTAcatheter balloon both dilates a stenotic lesion and simultaneouslyimpregnates a therapeutic agent into the vascular wall during inflation.In another embodiment, the present disclosure is particularly useful intreatment of peripheral vascular disease in vessels with long, diffuselesions, such as iliac, femoropopliteral, and tibial/below the kneearteries.

Peripheral vascular disease has several distinguishing characteristicsfrom its coronary counterpart even though the underlying atheroscleroticprocess is similar. First, the peripheral vasculature can range indiameter from 12 mm for iliac to less than 2 mm for tibial arteriescompared to coronary which can range from 1.5-4 mm. For most peripheralvascular disease, the lesions are longer and more diffuse whereas forcoronary artery disease, they are shorter and more focal. Also, thelocation of the target arteries is more variable, resulting in differentlength catheters. In addition, stents are particularly problematic inperipheral casculaturedue to stent fractures and low long term patencyrates. Other applicable vasculatures include renal, which has a diameterof about 4-7 mm and a length of about 15-40 mm, and intracranial, whichhas a diameter of about 1-3 mm and a length of about 5-30 mm.

Embodiments of the present disclosure pertain to both over-the-wire andrapid exchange PTA catheters. FIG. 1 is a general schematic of a PTAcatheter including, without limitation, an inflation lumen 10, aguidewire lumen 12, a shaft 14, and a balloon 16. Various embodiments ofthe present disclosure relate to methods for applying and adhering acoating containing a therapeutic agent to catheter balloons 16 usedgenerally in all angioplasty procedures, including balloon expandablestents.

The embodiments herein are not designed to be limiting but could becombined with other adherence techniques including, for example andwithout limitation, electrodepositing, pad printing, microspheres,nanotubes, dipping, spraying, brushing, powdering, dusting,vaporization, dripping, injecting, electrical activation of drugrelease, plasma treating, etc. The embodiments described herein caninclude coating compositions in a liquid, solid, gas, gel, slurry, etc.state as appropriate. Further, the embodiments described herein may beutilized at any appropriate state of balloon 16 manufacturing including,for example, extrusion, blow-molding, pleating, folding, after folding,and before or after placement of a protective sheath.

Various embodiments of the present disclosure pertain to an adherentcoating containing a therapeutic agent on the balloon 16 for inhibitingrestenosis after angioplasty. As an example, the coating is a blend ofiopromide and paclitaxel dissolved in solvents with minimal to noamounts of water to form a solution which is then applied to the balloon16. Solvents include, for example and without limitation, methanol,ethanol, acetone, isopropano, methyl ethyl ketone, ethyl acetate, butylacetate, butyl chloride, cholorform, diethyl ether, dimethyl sulfoxide,dimethyl formamide, tetrahydrofuran, glyderin, essential oils, water,mixtures thereof, etc. For example, the target concentration averagedrug range for paclitaxel is about 0.5-10.5 micrograms/mm² of totalballoon 16 surface area, more preferably about 2-6 micrograms/mm², andmore preferably about 3±10% micrograms/mm². The coating is dynamicallyreleased upon inflation of the balloon 16 and transferred to thearterial wall. After deft ion, the drug remains impregnated in arterialtissue to inhibit restenosis.

Dip coating may be used to coat catheter balloons 16. Dip coated ballooncatheters have a coating on the surface of the balloon 16 applied byimmersing the balloon 16 into a coating solution containing at least onesolvent and a therapeutic, such as for example, Paclitaxel and atransfer agent, such as Ultravist 370® contrast media as manufactured byBayer Schering Pharma. The external surface of the balloon 16 and theinternal surfaces of the folds of the balloon 16 are exposed to thecoating solution, filling the interstitial spaces of the folds under theaction of surface tension and gravity and coating the outside surfacesunder the action of surface tension. The balloon 16 is then removed fromthe solution and excess solution allowed to drain, after which thesolution is allowed to dry on the balloon 16 surfaces. In general, thisprocess is not capable of applying a uniform and quantitativelyreproducible coating on the balloon 16 surface and multiple dippings maybe required to increase the therapeutic concentration to its desiredlevel.

To address these issues, embodiments of the present disclosure orcombinations thereof provide for metering a specific amount of atherapeutic agent into the folds and/or onto the surface of the balloon16. As an example, the embodiments disclosed herein with or withoutmodification of the coating solution may enhance the standard dippingmethod to allow a single step process.

Embodiments of the present disclosure include a metered injectionprocessing which a predetermined amount of coating solution is appliedto a folded balloon 16 at one time, after which a protective sheath isplaced over the coated balloon 16. In one embodiment, an injectiondevice, such as, for example and without limitation, a precision glasssyringe 18, a pipette, a nozzle, etc., is filled with the exact amountof coating solution required to achieve the desired concentration of atherapeutic on the balloon 16. If necessary, the injection device couldbe refilled from a reservoir and additional coating solution added. Inan alternative, the concentration of the therapeutic in the coatingsolution is optimized. For examples using a syringe, see FIG. 2 and FIG.3. The needle 20 of the syringe 18 is placed in close proximity to theballoon 16 surface and the coating solution is applied to the balloons16 by depressing a plunger and moving the needle 20 over the surface ofthe balloon 16 to be coated. Once all required coating solution isapplied to the balloon 16, the balloon 16 is rotated for a short periodof time to obtain an uniform distribution of coating solution over thecoated surfaces and to allow the surface coating to partially dry. Aprotective sheath (not shown in FIG. 2 and FIG. 3) may be placed overthe balloon 16 and the remaining liquid solution is distributed in thefolds and the solution allowed to dry over time.

In further examples, two metered injection techniques for applyingsolution to folded balloons 16 to produce different coatingdistributions on the balloon 16 are disclosed. In the first technique,outside surfaces of a balloon 16 are coated uniformly by holding asyringe needle 20, for example, horizontally with the tip just slightlyabove but not touching the balloon 16 as shown in FIG. 2. The balloon 16is rotated continuously while solution is applied to the balloon 16 andthe syringe needle 20 moved axially along the balloon 16 length. Surfacetension wicks the coating solution from the syringe needle 20 onto theballoon 16. In the second technique, internal surfaces of balloon folds22 are coated by holding a syringe needle 20 vertically with its tip atthe entrance to the fold 22 as shown in FIG. 3. Coating solution isapplied into the folds 22 while the syringe needle 20 is moved axiallyalong the entrance to the fold 22. For balloons 16 with multiple folds22, the balloon 16 is then indexed to the next fold 22 and the processrepeated until all folds 22 have been filled. As an alternative,multiple injection devices may be used to fill all the folds 22 at onetime. At the completion of either technique, the balloon 16 is rotatedfor a short period of time to ensure uniform distribution of the coatingsolution in the folds 22 and/or partial drying f the surface coating.These two techniques can be combined to produce a coating distributionover both internal and external surfaces of a folded balloon 16. Thesemethods, used separately or in combination, provide the ability tocontrol both the amount of coating solution, i.e. therapeutic, and thelocation on a folded balloon 16.

Embodiments of the present disclosure can utilize technology to meternanoliter droplets onto the surface of a balloon 16 in a predefinedpattern. The technology works by using piezoelectric pressure pulses toforce liquid through a small, precision orifice to create tiny dropletsthat are expelled onto a surface. By controlling the magnitude of thepressure pulse, the size of a fluid droplet can be controlled veryaccurately. In this embodiment, coating solution fills a small chamberand an electrical signal is sent to a piezoelectric crystal, whichgenerates a pressure pulse to inject tiny droplets onto the surface of aballoon 16. A nozzle is moved in a fixed pattern over the surface of theballoon 16 to coat it uniformly with droplets. The liquid droplets areallowed to dry on the surface of the balloon 16 leaving behind aresidual pattern of dots that, in total, contain the required quantityof therapeutic agent to meet the target concentration.

By selectively coating only a portion of the balloon 16 surface, largervolume droplets may be placed on the balloon 16 surface that then dryinto a white powdery structure, which may be considered clinicallydesirable. Coating solution development has shown that thicker layers ofcoating may produce a more desirable coating structure. By placing smalldroplets in close proximity to one another, the uniformity of thecoating from a clinical perspective is likely not compromised becausethe drug diffuses over short distances in a coronary artery. By having apulse that injects the droplet onto the balloon 16, the need to provideprecise containers for distribution of the coating solution may beeliminated. In addition, because the droplets are so small, completedrying of the coating generally occurs in minutes rather than hours.

One embodiment of the present disclosure involves the configuration ofcatheter balloon 16 folds 22 to optimize the application, distribution,containment, and drying of a coating solution to obtain a predeterminedor metered concentration of a therapeutic agent within the folds 22. Thedesired results may be accomplished using commercially available foldingequipment and a custom conditioning process. The outcome is folds 22with a pre-determined volume and shape specific for every balloon 16diameter required for the final device and specific coating composition.This allows for an exact volume of a coating solution to be administeredto the folds 22. The solution is then optionally dried, sterilized andsent to the end user within the folds 22.

Historically, balloons 16 for catheters have been folded to lower theirprofile and facilitate entry into the vascular system for placement atthe target site for revascularization. Thus, minimizing the overallfolded diameter is a consideration in optimizing the folding process.However, for coated balloons 16 this dynamic is reversed because thefolds 22 act as containers for the coating solution. Therefore, thecontainers should be large enough to hold a dilute coating solution toachieve the desired therapeutic concentration but small enough todistribute the coating uniformly. A folded balloon 16 with three foldsis shown in FIG. 4. As can be seen from the figure, a folded balloon 16consists of pleats 24 that are pressed together and then wrappedsubstantially uniformly around the inner shaft 14 of the ballooncatheter. A closed space is formed by the inner surface 26 of the pleat24 to the outside surface 28 and the portion of the balloon 16 adjacentto the inner shaft 14. The fold 22 is characterized by a depth definedas the distance from the entrance 30 to the container to the fold 22 toits bottom 32, a width defined as the distance from the inside surface34 of the fold 22 to its outside surface 36, and a length defined as theaxial distance from the most distal point of the fold 22 to its mostproximal point (not shown). Each of these dimensions can be modified bythe balloon 16 folding process itself and optimized to maintain theconcentration of the therapeutic agent during delivery to the treatmentsite.

Of the three dimensions, fold 22 depth may have the most impact oncoating. Fold 22 depth considerations may be important for filling,retaining, distributing and drying the coating solution on the balloon16. The ideal depth may be a trade off between a shallow depth, whichallows for easy penetration and filling of the fold 22 with reducedability to retain the fluid, against a deeper depth which is moredifficult to fill but retains the coating solution more securely. Thisis a result of the interplay between the material, the surface tension,and viscosity of the solution. In general, higher surface tension andsolution viscosity may make penetration of the folds 22 more difficultbut allow for better retention. As a general rule, more concentratedcoating solutions will have both higher surface tension and higherviscosity. In an example, a fold 22 depth of approximately 1.5millimeters±50% may be, in one embodiment, an acceptable trade offbetween ease of filling and retention of coating solution.

A determinant in fold 22 depth is the number of folds 22 for a givenballoon 16 size. More folds 22 result in shallower fold 22 depths. Thestandard folding process uses three folds 22 for all balloon 16 sizes.As can be seen in Table 1 the fold 22 depth varies from 0.16 mm for a2.0 mm balloon 16 to 3.92 mm for a 10 mm balloon 16. This change in fold22 depth has resulted in coating variability when using a dippingprocess. Smaller diameter balloons 16 are generally easier to fill whilelarger diameters are generally more difficult. During validation studiesof the automated drip coating system, it was difficult to obtainadequate distribution of coating in the folds 22, especially on largerballoons 16. To eliminate this non-uniformity in coating distribution,the number of folds 22 is changed with each balloon 16 diameter andcoating composition to better optimize the fold 22 depth. In an example,Table 1 shows the number of folds 22 for each balloon 16 diameter usinga fold 22 depth of approximately 1.5 millimeters.

In conjunction with the fold 22 depth, the fold 22 width may becontrolled to obtain the proper sized container to hold the volume ofcoating solution required to obtain the desired therapeuticconcentration on the balloon 16. For example, in conjunction with theabove fold 22 depths, a fold 22 width of approximately 0.11 mm±100%provides a fold 22 container that will allow enough solution with ahigher concentration of therapeutic agent, for example a 150 mg/mlsolution, to be applied to a balloon 16 in one application session. Inthis example, the fold 22 could be completely closed or have a fold 22width of 0.22 mm, which would allow easier application and increaseddrug load.

TABLE 1 Fold Depths Balloon Shaft Dia Depth Depth Dia (mm) # Folds (mm)# Folds (mm) 4 Fr 2.0 3 0.16 2 0.29 4.0 3 1.18 3 1.18 5.0 3 1.71 4 1.256.0 3 2.23 5 1.30 5 Fr 4.0 3 1.00 3 1.00 5.0 3 1.52 3 1.52 6.0 3 2.05 41.51 7.0 3 2.55 5 1.49 8.0 3 3.07 6 1.48 6 Fr 9.0 3 3.39 7 1.39 10.0 33.92 8 1.40During the coating process, the exact amount of coating solutionrequired for a give n fold 22 may be determined. For example, Table 2shows the volume of coating solution required for differentconfigurations and different solution concentrations. The volume rangesfrom 21 microliters for a 2.0×20 mm balloon 16 up to 670 microliters fora 10.0×150 mm balloon 16 while using a low therapeutic concentrationsolution, for example a 30 mg/ml drug coating solution. The balloon 16fold 22 for each balloon 16 size may then be tailored to match thisfluid volume. This process involves developing the balloon 16 foldingprocess to yield the depth and width that are required for the specificcoating solution formulation being used. Alternatively, theconcentration of coating solution can be varied to match the fold 22volume.

TABLE 2 Solution Requirements Balloon 30 mg/ml Solution (μl) 90 mg/mlSolution (μl) 180 mg/ml Solution (μl) Dia Balloon length (mm) Balloonlength (mm) Balloon length (mm) (mm) 20 80 150 20 80 150 20 80 150 2.021 71 130 7 24 43 4 14 26 3.0 34 110 198 11 37 66 7 22 40 4.0 40 141 25813 47 86 8 28 52 5.0 52 178 325 17 59 108 10 36 65 6.0 65 266 392 22 89131 13 53 78 7.0 79 314 460 26 105 153 16 63 92 8.0 94 295 529 31 98 17619 59 106 9.0 109 336 599 36 112 200 22 67 120 10.0 126 377 670 42 126223 25 75 134

The placement of coating solution only in the folds 22 of balloons 16allows for the ability to place a protective sheath over the balloon 16while the solution is still liquid without damaging or removing coatingsolution from the balloon 16. In addition, the placement of theprotective sheath also provides a mechanism for maintaining the desiredfold width that in turn may allow for uniform distribution along thelength of the fold 22. Also, protection of the dry coating duringsubsequent steps of manufacturing and preparation for clinical usage maybe achieved. The folds 22 act as a mechanical protector against abrasionduring clinical preparation and also for introduction through anintroducer and travel through the vascular system to the targetrevascularization site. This allows for delivery of a desiredtherapeutic concentration at the delivery site. For balloons 16 thathave a significant percentage of the coating on the outside surfaces,the placement and removal of the protective sheath as well as themechanical abrasion associated with entry though a vascular introduceraffords an opportunity for loss of coating from the balloon 16 surfaces.Having the correct container size may allow for the exact amount ofcoating solution to be applied to the balloon 16 in one applicationsession. Filling the container so that it is completely full mayautomatically distribute the coating solution within the balloon 16folds 22 which, when the coating solution dries, may give a more uniformdistribution of the residual solid material; thereby providing moreuniform application of the therapeutic to the application site. Sincethe balloon 16 folds 22 are accurately sized and a metered amount oftherapeutic coating solution is applied, the concentration oftherapeutic is more consistent from balloon 16 to balloon 16.

The folding configurations described above and embodied in the presentdisclosure may be used with any application of a coating, including forexample a therapeutic agent, onto a catheter balloon 16, such as,without limitation, metered or dip coated applications.

A further embodiment of the present disclosure includes the use of aspecifically-sized protective sheath 42 to distribute the coating,including for example a therapeutic agent, on a catheter balloon 16. Thespecifically-sized protective sheath 42 may be substantiallyspecifically-sized for a given balloon 16 diameter. See FIG. 5. Thisembodiment may be easily applied and may be effective when used inconjunction with a metered application method, but can also be used withany application method, including for example the dip coating method forapplication of a therapeutic agent on a catheter balloon 16. Forexample, if a coating solution is only injected into the folds 22, thespecifically-sized protective sheath 42 may be applied immediately aftercoating. If the coating solution is applied either partially orexclusively to the outside surfaces of the balloon 16, then a short airdrying step may be necessary to allow the surface of the coating toharden to the point where placement of the specifically-sized protectivesheath 42 does not abrade the coating from the balloon 16. Becauseexternal surfaces dry more rapidly than internal surfaces of the folds22, placement of the specifically-sized protective sheath 42 mayredistribute the liquid coating solution in the folds 22 more uniformly.Other techniques, such as plasma treating for example, may helpfacilitate this process.

Optionally, the specifically-sized protective sheath 42 has spiral slits44 around the circumference allowing for both uniform distribution andfaster drying time. See FIG. 6A. FIG. 6B shows a non-slottedspecifically-sized protective sheath 42. One the balloon 16 (not shown)is in place, the ends of the specifically-sized protective sheath 42 aretwisted with opposing force using a ratcheting mechanism to constrictthe tubing, causing slight pressure on the balloon 16 surface. See FIG.6A. The pressure may reduce relaxing of the balloon 16 duringsterilization, shipping, and storage. The specifically-sized protectivesheath 42 is held in place with at least one closing band 46 at each endusing a hooking mechanism 48. The specifically-sized protective sheath42 is installed over a drug coated balloon 16, minimizing the damage tothe therapeutic coating. The therapeutic coatings are not damaged byinstallation and removal of the specifically-sized protective sheath 42.The specifically-sized protective sheath 42 also provides standardprotection during processing and treatment. Furthermore, thespecifically-sized protective sheath 42 is breathable, particularly withslits 44, allowing for drying of the coating while in a protected state.

Because the coating solution is in contact with the balloon 16 surfacefor a longer period of time, under the influence of thespecifically-sized protective sheath 42 better adhesion may be obtainedbetween the balloon 16 and the dried coating. The specifically-sizedprotective sheath 42 placed over the balloon 16 shortly after theapplication of the coating solution allows the balloons 16 to be handledsooner compared to a multiple dip process, thereby increasing productionand decreasing costs. Because the coating solutions is still liquid, theballoon 16 profile may be made smaller and more uniform to mitigate theeffects of distortion caused by solvent interaction with the balloon 16material.

In another embodiment, a specifically-sized protective sheath 42 isplaced over the catheter balloon 16 first and then the coating appliedinside the folds 22. For example, metered injection could be performedusing a syringe, cannula, or tube covering the end of the device. Thespecifically-sized protective sheath 42 may be specifically-sized suchthat the folds are not completely closed. In an example, thespecifically-sized protective sheath 42 has a diameter about 1-12thousandths of an inch larger than the diameter of the balloon 16. Inaddition, the specifically-sized protective sheath 42 may besubstantially sized to obtain a desired concentration of a therapeuticagent on the catheter balloon 16 with one application of a coatinghaving a given composition and therapeutic agent. The coating is thenforced into the specifically-sized protective sheath 42 and thus intoall the folds 22. The volume necessary to fill the folds 22 may becalculated or visually determined. Drying may occur over time, forexample within 24 hours in ambient air, or optionally in an oven at50±20 degrees Celsius for 2-4 hours.

Other embodiments enhance the dipping process. A vacuum or a pressure ora combination thereof may be used to force the coating into the folds 22either before or after the specifically-sized protective sheath 42 isplaced over the balloon 16, i.e. pressurized dip coating. For example, aballoon catheter is placed into a coating solution 50 in a pressurechamber 52, a pressure is applied forcing the coating into the folds 22of the balloon 16, and after the pressure is removed the catheters areremoved to dry. See FIG. 7A and FIG. 7B. In an alternate method, theballoon 16 is rotated in the coating solution 50 in a direction thatcauses the folds 22 to open slightly for coating deeper into the folds22. See FIG. 8. Optionally, the balloon 16 is pulled through the coatingsolution 50 length-wise as it is rotated to provide a more uniformcoating. Also, optionally, the balloon 16 is slightly inflated prior toplacing in the coating solution 50 to maximize and to improve theuniformity of the coating. These embodiments in particular, alone or incombination, may enhance the dipping method to a single step.

A further embodiment for applying the coating inside the folds 22comprises the use of at least one spacer 54 or a wick 56 to draw acoating solution 50 into at last one fold 22. See FIG. 9 and FIG. 10.The spacers 54 may be any hard, inert material, for example plasticssuch as Teflon® or Delran® or metal such as aluminum, which opens thefolds at least partially. In an example, the spacers 54 are aluminumrods. See FIG. 9. The spacers 54 are positioned at the proximal and/ordistal end of the balloon 16 and placed into the folds 22 during thefolding process or after the balloon 16 is folded with or without aprotective sheath. In one embodiment, the spacers 54 are substantiallylong enough to hold the folds 22 at least partially open and may be thelength of the balloon 16. The width of the spacers 54 is wide enough tohold the folds 22 at least partially open and may be as wide as thewidth of the fold 22. In an example for a 4.0×20 mm balloon, the spacersmay be 1.1 mm wide and 20 mm long. Spacers 54 may be used with anycoating application method, including with methods that require thefolds 22 to be slightly open, such as the dipping method. After coating,the spacers 54 may be removed by hand or by a mechanical means. IF usinga method requiring a bath, the spacers 54 may be removed in the bath. Inthe example of aluminum rod spacers 54 inside the folds used with thedipping method, the spacers 54 may be slipped out of the folds 22 duringor directly after dipping, thus allowing the coating solution to fillthe void, but may be left in place long enough to hold the folds 22open.

The wick 56 may be, for example and without limitation, anyplastic-based rope-like substance, a nylon material, a cotton material,an organic material, any synthetic materials, or a combination thereof.The wick 56 may be placed into the folds 22 during folding on the distalend of the balloon 16. See FIG. 10. Wicks 56 may be used with anycoating application. The wick 56 draws the coating solution into thefolds 22 by capillary action, so that the folds 22 are filled. The wick56 may be removed either in a bath solution if one is used or out of abath solution and either by hand or by mechanical means. The wick 56 isoptionally removed after coating but before air-drying, or as analternative the wick is left in to promote faster drying as air is blownacross (FIG. 10). Use of spacers 54 or a wick 56 promotes meteredapplication of a specific amount of coating, such as a therapeuticagent.

Another embodiment for applying the coating inside the folds 22 pertainsto a balloon 16 conditioning process whereby the balloon 16 partiallyopens when submersed in a bath of at least one solvent,such as, forexample and without limitation, ethanol, methanol, isopropanol, acetone,diethyl ether, diisopropyl ether, and chloroform before application ofthe coating. The opening of the balloon folds 22 may also be promoted byusing one or more of such solvents in the formulation of coatingsolution. In an alternate embodiment, the solvent(s) may be sprayed onto partially open the folds 22. The solvent(s) may be applied in onesteps or multiple steps. In an example of a two-step process, theballoon 16 is first dipped into one solvent, such as acetone, andsubsequently dipped into a second solvent, such as ethanol. Thetherapeutic coating may be applied by any method. If desired, theballoon 16 may be refolded after coating by the application of thespecifically-sized protective sheath 42.

Additional embodiments of the present disclosure pertain to techniquesfor allowing optimization of balloon 16 performance, coating structure,and coating adherence independently by providing an intermediatematerial layer 58 on the balloon 16 to act as a bridge between theballoon 16 and therapeutic coating 60. See FIG. 11. The intermediatelayer 58 adheres to the balloon 16 material on one side and provides foradherence of the therapeutic coating 60 on the other side. This may beuseful for hydrophilic drugs, such as Doxorubicin, and others that havea tendency to be lost during the balloon 16 insertion process. Otherexamples of hydrophilic drugs include, without limitation, caffeine,nicotine, netilmicin, dopamine, sugar, sugar alcohols, other organicneutral substances, lipophilic amino acids, salts of organic andanorganic acids and bases, contrast mediums or dyes commonly used inmedicine, coagulation inhibitors such as heparin, platelet aggregationinhibitors such as acetylsalicylic acid, and salicylic acid. Balloon 16performance characteristics such as compliance and burst strength may beoptimized independently from therapeutic coating 60 characteristics suchas structure and adherence.

Several different methods may be used to obtain the intermediate layer58. In an example, a thin, second layer of material is extruded onto theballoon 16 tubing before the balloon 16 is formed. In another example,the two materials are extruded independently and are adhesively bondedtogether after balloon 16 forming but before folding and heat setting.In another example, material is evaporated and deposited onto theballoon 16 surface via an electronic excitation process. This processmay allow for plasma deposition to be controlled by choice parameters.Examples of materials that may require such treatment include withoutlimitation Teflons, Polyethylene terephthalate (PET), Urethanes, andPolypropylene (PP). In an example, a Pebax Nylon is deposited as a thinlayer over a PET based balloon 16 resulting in a stiff solid balloon 16with substantially similar release characteristics as the standardballoon 16. Another example is to plasma treat the balloon 16 surfacebefore or after folding with a nonpolymer forming plasma. In thistechnique, the balloon 16 surface is activated via formation of newfunctional groups or creation of micro roughness on the surface, whichmay aid adhesion of the therapeutic coating 60 to the balloon 16surface.

A balloon 16 material may be chosen to meet performance criteria such asburst pressure and compliance and the therapeutic coating 60 may bedesigned to meet compositional and morphological criteria. As a result,therapeutic coating 60 adherence to a balloon 16 surface is a by-productof the optimization of balloon 16 material and therapeutic coating 60characteristics. However, adherence may be clinically important fordelivery of the therapeutic to the target site for revascularization.From a design perspective, it may be desirable to optimize balloon 16performance, therapeutic coating 60 structures, and therapeutic coating60 adherence independently. As an example, if the current balloon 16material were changed, development of a new therapeutic coating 60 maybe required to maintain the same clinical effectiveness of thetherapeutic coating 60 as with the current material. This embodimentallows balloons 16 with much different structural properties thancurrent balloons 16, i.e., balloons which are more compliant but havethe same burst pressure, to be tailored to match that of the currentmaterial by the addition of an intermediate layer 58. The intermediatelayer 58 may allow the use of the therapeutic coating 60 and process forapplying a therapeutic coating 60 to the balloon 16 providing animproved delivery platform, such as better release characteristics, anda clinically more effective therapeutic coating 60.

Further embodiments comprise the addition of a priming layer to thecatheter balloon 16 to increase drug adherence or enhance deviceproperties. Examples of priming layers include, without limitation,iopromide or radiopaque materials, adhesive, hydrogel, polymericmaterials, biodegradable layers, biocompatible layers, hydrophilicmaterials, lubricious materials, epoxies, etc. In an example, thecatheter balloon 16 is first coated with iopromide, then coated with thetherapeutic agent, and finally coated with a second layer of iopromide.In another example, the catheter balloon 16 is first coated with ahydrogel or adhesive and then coated with the therapeutic agent. In analternative example, the therapeutic agent is mixed with the hydrogel oradhesive before coating. In another example, the therapeutic agent ismixed with iopromide or Ultravist® contract media.

In one embodiment, a catheter balloon 16 is coated with a soluble film62 comprising a therapeutic agent, such as paclitaxel. See FIG. 12.Example materials used to make the soluble film 62 include, withoutlimitation, porcine, bovine, aquatic vertebra (fish), avian, and Ovobased gelatin, such as pork skin derivatives and Gelfoam, gelatinizedstarch, cellulose, fruit/vegetable base, for example cooked apples oragar, and any other organic polymer. In an example, the materials are inpowdered form and mixed with water or other solvents to produce thesoluble film 62. In another example, the solution is mixed with 30 mg/mlof Paclitaxel, 100 ml of purified water, 2 ml of Ultravist® contrastmedia and 0.25oz of gelatin. The solution is placed into molds in whichthe base solidifies and forms the strips or tubes, which are insertedinto the folds 22 or applied over the folded balloon 16. The dimensionsof the strips may have a thickness of about 0.05 mm to about 1 mm, widthof about 0.05 mm to about 4 mm and a length that covers the length ofthe balloon 16 intended to coat. The dimensions of the tubes may have athickness of about 0.05 mm to about 1 mm, a diameter of about 1 mm toabout 1 cm, and a length that covers the length of the balloon 16. Theamounts shown above may be adjusted using more or less paclitaxel, moreor less Ultravist® contrast media or more or less gelatin. In yetanother example, fruit and/or vegetables are reduced down to produce athick puree base. The base containing 100 ml of reduction may be mixedwith 50 mg/ml of Paclitaxel and 3 ml of Ultravist® contrast media, whichis placed in molds for strips or tubes. The molds may be dried in anoven at 140 degrees F. for 3-12 hours and/or a dehydrator. The solublefilm 62 may then be applied to the balloon 16. In an alternateembodiment, the balloon 16 is dipped into the base before drying. Theballoon 16 may be dried and have a soluble film 62 over the surface. Inanother embodiment, the base is sprayed on the balloon 16.

The soluble film 62 may be applied over the formed balloon 16 and/orfolded along with the balloon 16. The soluble film 62 may be appliedpost pleating prior to folding. See FIG. 12A and FIG. 12B. The solublefilm 62 may be applied in the folds 22 (FIG. 12C), over the foldedballoon 16 (FIG. 12D), or a combination (FIG. 12E) before the optionalprotective sheath. The soluble film 62 may be in the form of stripswrapped around the balloon 16 vertically or axially (FIG. 12F-FIG. 12H)or can coat the entire balloon 16 (FIG. 12I). The strips of soluble film62 may be in at least one fold of the folded catheter balloon 16. Thestrips may be placed in at least one fold 22 of the catheter balloon 16by sliding the strips between the folds 22 or in an alternative examplethe soluble film 62 strips may be folded into the folds 22 during thefolding process, for example through placement of soluble film 62 stripson the folding heads. In another example, soluble film is applied duringthe extrusion process of the base balloon 16 material. As the extrusionmedia (tubing) exits the extruder a separate process step may be inplace where the soluble film 62 tube is slid over the nylon or othermaterial balloon 16 tubing. Alternatively, the soluble film 62 may beapplied by any combination of methods.

In one embodiment, the thickness of the soluble film 62 is within thefolding range such that the overall catheter profile does not increase.The soluble film 62 may be wetted by the user prior to use or the bloodin the vessel may be sufficient to dissolve the soluble film 62 at thetarget location. The soluble film 62 may attach to the vessel wall anddissolve over time or may remain attached to the catheter and leach thetherapeutic agent out at the target location. In an example usingPaclitaxel and Ultravist® contrast media, the Ultravist® contrast mediaacts as the carrier or excipient to allow for the Paclitaxel uptake intothe vessel wall. The time frame may at a minimum about 30 sec to 2-3min. In this example, since the soluble film 62 could be sticky, it maybe deposited against the wall like a gel or thick film. Depending on thethickness of the soluble film 62, it could dissolve over 30 sec up to 24hours. In another example, the soluble film 62 remains in place formonths as the soluble film 62 becomes part of the vessel withtherapeutic release over 30 days, similar to a stent. By way of any ofthese variations or combinations thereof, the metered concentration ofthe therapeutic agent remains consistently within the dosing range.

Embodiments of the present disclosure provide the combined ability tocontrol both the amount of therapeutic agent and its distribution on afolded catheter balloon 16 or other medical device. The ability tocontrol these two aspects of a coating is non-existent in the currentdipping process. In an example, a target therapeutic concentration canbe placed on the balloon 16 within 0.1 micrograms per square millimeter.As a result, only the required amount of therapeutic necessary toachieve the desired therapeutic effect is applied to the balloon 16.This optimizes the treatment process for the patient. The control oftherapeutic location allows for optimization of therapeutic distributionto obtain the desired clinical effect while also maximizing the abilityto deliver the therapeutic to the target site for revascularization. Byplacing more therapeutic in the folds 22 of a catheter balloon 16, anatural protection is afforded for, for example, the loss of the driedcoating from abrasion during manufacturing, clinical preparation andintroduction of the catheter into the vascular system through ahomeostasis valve introducer. In another example, by reducing theapplication process to a single injecting, manufacturing times can bereduced and the amount of toxic waste and its handling can be minimized,all of which reduces manufacturing costs. These methods can use anysolution chemistry with only minor modification to the applicationsystem. These features may provide a high degree of flexibility totailor the solution chemistry to enhance the effectiveness of the driedcoating.

EXAMPLES Metered Injection

The following discussion illustrates non-limiting examples ofembodiments of the present disclosure. Techniques for metering an exactvolume of coating solution onto catheter balloons can use, for example,precision glass syringes, such as those manufactured by HamiltonCompany. The syringe consists of a glass barrel with a precision bore,mating plunger with an accurately machines Teflon® seal and a distalfluid connector with either a luer taper, fixed needle or removableneedle. The Hamilton Series 700 syringes are available in volumesranging from 5 to 500 μl and the Series 1000 syringes ranging from 1 to100 ml.

To hold and rotate the balloon, a custom mounting fixture was designedcontaining the following elements:

-   -   Touhy Borst Gasket to hold the shaft of the balloon catheter        near the proximal balloon blood;    -   Guidewaire Holder to support the distal end of the guidwire used        to sitffen the balloon section of the catheter;    -   Catheter Drive Pulley to interface with the motor to rotate the        balloon;    -   DC Motor to rotate the balloon;    -   Motor Drive Pulley and Belt to interface with the Catheter Drive        Pulley and rotate the balloon at 60 rpm.        The fixture was designed for use in conjunction with a        stereomicroscope.

A metering system may be a manual syringe application method to dispensecoating solution onto a balloon. This method requires refilling of asyringe after every application of solution. Additionally, the refillingprocess exposes coating solution to air, causing evaporation of lowerboiling point solvents and subsequent destabilization of the coatingsolution. To enhance accuracy and promote solution stability, anapplication system was developed using a syringe pump, precisionsyringe, three-way valve and a solution reservoir. This system enhancedthe metering process by using a syringe pump that can repeatedly movethe plunger a fixed distance to precisely dispense a predeterminedvolume of solution onto the balloon. At the center of the system is amicroliter dispensing pump that uses a Hamilton precision glass syringeas described above. The distal end of the precision syringe interfaceswith a three-way valve that can select a fluid reservoir for refillingor fluid tubing for delivery of solution. At the other end, the plungerinterfaces with a sliding mechanism on the syringe pump which is used topush the plunger an accurate distance during dispensing. Using acustom-designed linear screw driven by a stepper motor and a precisionglass syringe, solution injection volume variability was reduced to lessthan ±5 percent.

Approximately 30 catheters of different balloon dimensions and solutioncompositions were made for testing in a first study. For each lot ofcatheters, high performance liquid chromatography (HPLC) testing wasdone on 5 balloons with stents and 5 balloons without stents todetermine the concentration of paclitaxel and iopromide on each balloon.The testing was done using the same protocols used historically on dipcoated balloons. The results are summarized in Tables 3 and 4.

TABLE 3 Preclinical Study Paclitaxel Concentration Paclitaxel (μg/mm²)Without Stent Paclitaxel (μg/mm²) With Stent Avg Min Max Var Avg Min MaxVar Loss 3.5 × 20 Exp 4 4.52 4.23 4.78  6.1% 4.31 3.85 4.61  8.8%  5%Exp 3 4.54 4.39 4.70  3.4% 4.43 4.38 4.45  0.8%  3% Exp 2 4.54 4.34 4.77 4.7% 4.21 3.99 4.65  7.8%  7% Exp 1 5.11 4.64 5.41  7.5% 4.69 4.43 4.91 5.1%  8% Control 2.24 1.59 2.90 29.2% — — — — — 3.0 × 20 Exp 4 4.694.60 4.77  1.8% 4.52 4.12 4.76  7.1%  4% Exp 3 4.74 4.71 4.79  0.8% 4.604.47 4.70  2.5%  3% Exp 2 4.87 4.77 5.10  3.4% 4.26 3.60 4.53 10.9% 12%Exp 1 6.40 6.05 7.01  7.5% 5.36 4.39 5.89 14.0% 16% Control 2.18 1.682.52 19.3% — — — — —

TABLE 4 Pre-clinical Study P/I Ratio P/I Ratio P/I Ratio Without StentWith Stent Avg Min Max Var Avg Min Max Var 3.5 × 20 Exp 4 1.68 1.63 1.794.7% 1.68 1.64 1.76 3.4% Exp 3 1.65 1.64 1.65 0.3% 1.68 1.66 1.69 0.7%Exp 2 1.62 1.57 1.64 2.2% 1.62 1.61 1.64 0.7% Exp 1 1.69 1.64 1.70 1.6%1.69 1.64 1.78 4.1% 3.0 × 20 Exp 4 1.64 1.62 1.65 0.9% 1.64 1.61 1.651.4% Exp 3 1.66 1.62 1.65 0.9% 1.67 1.67 1.70 1.1% Exp 2 1.63 1.61 1.640.7% 1.64 1.61 1.68 2.0% Exp 1 1.70 1.68 1.68 0.2% 1.74 1.66 1.80 4.2%

Excluding the control, the results for unstented balloons show anincrease in drug content and reduced intralot variability compared todip coating. Pooling results for experiments 1 thru 4 and both balloonsizes gives an average paclitaxel content of 4.6 μg/mm² with a variationof ±9.4% compared to 2.2 μg/mm² with a variation of ±30%. The P/I ratio,which is the ration between paclitaxel and iopromide on the balloon,averaged 1.65 with a variation of ±6.6%. The P/I ratio for dip coatingwas 2.0 with variation of ±25% so the average are not comparable. Theseexamples were made as six mixings of three different coating solutionsover three days; thus demonstrating the repeatability of the process.

For stented balloons, the average paclitaxel concentration was 4.4μg/mm² with a slightly higher variation of ±13.5%. This represents adrug loss of approximately 5.7%. The P/I ration was unchanged betweenstented and unstented balloons.

A coating specification study corresponding to the above study was alsodone. For this study, rapid exchange PTCA catheters with 3.5×20 mm and3.0×20 mm balloons were coated with solutions. The total solution volumeapplied to the balloons was determined using 5 μg/mm² drug concentrationwhich provided a margin of safety above the minimum acceptable value of2.0 ξg/mm². Solutions were injected into the folds and applied to theballoon surface using the syringe pump technique described above. Table5 gives the solution specifications for each balloon diameter andsolution configuration. For configuration 1, approximately two-thirds ofthe solution was placed in the folds and one-third on the outer surface.For configuration 2, the solution was placed only in the folds with somesolution reaching the outer surfaces naturally.

A total of 60 catheters with 3.5×20 mm balloons and 40 catheters with3.0×20 mm balloons were coated. After the coating dries, stents werecrimped onto the coated balloons and the catheters were processedthrough final assembly, packaging and sterilization using standardmanufacturing procedures. At the completion of manufacturing, chemicalanalysis was done on both unstented and stented balloons.

TABLE 5 Coating Specifications TOTAL PER OUT- SOLUTION FOLD SIDE OUTSIDECONFIGURATION (μL) (μL) (μL) APPLICATIONS 3.5 × 20 MM-30 UNITSConfiguration 2 10.5 3.5 NA NA Configuration 1 17.5 4.0 5.5 1 3.0 × 20MM-20 UNITS Configuration 2 8.4 2.8 NA NA Configuration 1 14.0 3.0 5.0 1

During coating, the feasibility of two concepts of a semi-automatedcoating system was confirmed: air-free exchange process for mechanicallyrefilling the glass syringe and use of a precision screw coupled to astepper motor to precisely move the plunger of a glass syringe.

In the first study, solution instability was encountered which wasattributed to the constant exposure of solution to air during manualrefill of the metering syringe after each fold. During the coatingspecifications study, a closed loop system was used with a largerplastic syringe acting as a reservoir for filling the smaller glasssyringe. The only contact with air was the initial filling of bothsyringes. Subsequent fillings were done via a 3-way valve and withdrawalfrom the reservoir. No visible precipitations or coating segregation wasobserved during coating.

During the coating specifications study, glass slides were made aftereach group of five balloons. 45 μl drops of solution were metered ontothe slide and the net weight gain measured after the solution dried. Atotal of 13 slides for each configuration were completed and the resultsshown in Table 6.

TABLE 6 Configuration Variability Analysis WEIGHT (μg) WEIGHT (μg)CONFIGURATION THEORY AVG ACCURACY MIN MAX RANGE Configuration 1 6.6 6.82.9% 6.7 7.1 ±2.7% Configuration 2 10.9 11.1 1.4% 10.7 11.5 ±3.5%

The results indicate a mixing error of less than 3% and repeatabilityover two hours and 60 balloons of ±3.5%. If the accuracy andrepeatability are combined, the cumulative accuracy is ±5% which iswithin the target tolerance of 25.0% for the entire coating process.

For each lot of catheters, high pressure liquid chromatography (HPLC)was performed on 5 balloons with stents and 5 balloons without stents todetermine the concentration of paclitaxel and iopromide on each balloon.Testing was performed using the same protocols as the dip coatedballoons. The results are summarized in Tables 7 and 8 and showngraphically in FIG. 13.

TABLE 7 Coating Specification Study-Paclitaxel Concentration Paclitaxel(μg/MM²) Without Stent Paclitaxel (μg/MM²) With Stent Avg Min Max VarAvg Min Max Var Loss 3.5 × 20 Configuration 2 4.60 4.48 4.73 2.7% 3.452.81 3.83 14.8% 25% Configuration 1 4.97 4.78 5.13 3.5% 4.64 4.53 4.76 2.5%  7% 3.0 × 20 Configuration 2 4.88 4.82 4.94 1.2% 3.31 2.82 3.8715.9% 32% Configuration 1 4.96 4.89 5.03 1.4% 4.11 3.94 4.28  4.1% 17%

Coating Specification Study-P/1 Ratio P/I Ratio P/I Ratio Without StentWith Stent Avg Min Max Var Avg Min Max Var 3.5 × 20 Configuration 2 1.671.66 1.68 0.5% 1.61 1.57 1.65 2.5% Configuration 1 1.62 1.60 1.64 1.1%1.62 1.60 1.63 1.2% 3.0 × 20 Configuration 2 1.67 1.63 1.68 1.6% 1.651.60 1.71 3.4% Configuration 1 1.63 1.61 1.67 2.0% 1.58 1.55 1.64 3.0%

the results for unstented balloons show an increase in drug content andreduced intralot variability compared to dip coated balloons andsomewhat better than the first set of experiments. The pooled resultsfor both diameters and solution configurations gave an averagepaclitaxel content of 4.9 μg/mm² with a variation of 35 6.2% compared to4.6 [g/mm² with a variation of ±9.6% for first set of experimentsballoons and 2.2 μg/mm² with a variation fo ±30% for dip coatedballoons. The P/I ratio average 1.65 with a variation of ≅2.4% comparedto the same value but a variation of 6.6% for the first set ofexperiments.

For stented balloons, the pooled paclitaxel concentration was 3.88μg/mm² with a variation of ≅25.2%. This represents an average drug lossof approximately 20%, higher than the first study. This change isessentially in Configuration 2 data. If only Configuration 1 data areincluded, then the numbers are 4.38 μg/mm² with a variation of ±6.0%which represents a loss of 11.6% from stenting.

As shown, results were similar for both studies. Similar results wereobtained from studies performed using a different balloon composed ofdifferent materials, thus indicating the metered injection method isuseful for various balloon materials and types.

Spacers

Hard, inert spacers may be used to enhance coating of the folds of acatheter balloon. In an example, DeIrin® spacers having a width of 0.11mm were used. The spacers were inserted at the distal end of thecatheter balloon folds during the folding process. The balloon catheterswere subsequently dip coated with a single dip in a standard paclitaxelcoating solution bath. After during, HPLC analysis was performed todetermine the drug concentration on the devices. The goal of this studywas to have a mean paclitaxel value of 1.5 ug/mm² and a P/I ration of2.0.

TABLE 9 Spacer Study Results Paclitaxel Iopromid [μg/piece] [μg/piece]Paclitaxel/Iopromid Mean Value 1.57 .793 1.99 Standard 10.89 9.25 0.09Deviation

The results, as summarized in Table 9, indicate a mean value of 1.57ug/mm² of paclitaxel and an overall P/I ration of 1.99. These resultsdemonstrate that the use of spacers provides a means to maintain foldwidth to enhance coating and produce desired coating results, includingdrug concentration. In addition, the use of spacers can decreasemanufacturing time and costs by decreasing the number of dips requiredby the dip coating method to a single dip.

The present disclosure has been described with reference to specificdetails of particular embodiments thereof. It is not intended that suchdetails be regarded as limitations upon the scope of the disclosureexcept insofar as and to the extent that they are included in theaccompanying claims.

1-46. (canceled)
 47. A catheter balloon comprising an intermediate layerbetween said catheter balloon and a therapeutic coating.
 48. Thecatheter balloon of claim 47, wherein the intermediate layer is selectedfrom the group consisting of Teflon, PET, PP, Pebax, Urethane, andNylon.
 49. A method of coating a catheter balloon with a therapeuticagent, said method comprising placing an intermediate layer between saidballoon and said therapeutic agent.
 50. The method of claim 49, whereinthe step of placing comprises extruding a thin, second layer of materialonto a balloon tubing before said catheter balloon is formed.
 51. Themethod of claim 49, wherein the step of placing comprises adhesivelybonding said intermediate layer to said catheter balloon after extrusionof said catheter balloon but before folding and heat setting of saidcatheter balloon.
 52. The method of claim 49, wherein the step ofplacing comprises plasma depositing said intermediate layer.
 53. Themethod of claim of claim 49, wherein the intermediate layer is selectedfrom the group consisting of Teflon, PET, PP, Pebax, Urethane, andNylon. 54-69. (canceled)
 70. The catheter balloon of claim 47, whereinsaid therapeutic agent is a restenosis-inhibiting agent.
 71. Thecatheter balloon of claim 70, wherein said therapeutic agent ispaclitaxel.
 72. The catheter balloon of claim 47 which is a foldedballoon.
 73. The catheter balloon of claim 47, wherein the foldedcatheter balloon has a specific diameter, wherein said catheter balloonhas a specific number of folds with a predetermined volume and shape.74. The catheter balloon of claim 73, wherein said predetermined volumeand shape are determined by a fold depth and a fold width.
 75. Thecatheter balloon of claim 74, wherein said fold depth is about 1.5millimeters ±50%.
 76. The catheter balloon of claim 74, wherein saidfold width is about 0.11 millimeters ±100%.
 77. The method of coating acatheter balloon of claim 49, wherein said therapeutic agent is arestenosis-inhibiting agent.
 78. The method of coating a catheterballoon of claim 77, wherein said therapeutic agent is paclitaxel. 79.The method of coating a catheter balloon of claim 49, wherein thecatether balloon is a folded balloon.